Alcohol abuse and alcoholism are strongly correlated with an increased incidence of hypertension and its associated complications, such as stroke. The mechanism(s) for this effect of alcohol is unknown. Ethanol has been shown to directly contract large vessels in vitro and to alter the response produced by other vasoconstrictors. Tolerance develops to these actions of ethanol. It has been postulated that the endothelial cells lining blood vessels release a factor, termed endothelium-derived relaxing factor (EDRF), whose function may be the regulation of flow and pressure. We have recently demonstrated that the tolerance which develops to ethanol-induced contraction of the aorta, after a short period of intoxication, is dependent upon the endothelium and is mediated by the release of EDRF. The purpose of this proposal is to continue our investigation of the role played by endothelial cells in the vascular effects of ethanol. These studies will develop, in vivo and at physiologically relevant concentrations of ethanol, data which correlates the action of ethanol in microvessels with our previous in vitro observations in the aorta. In particular, we will test the following hypotheses (a) that EDRF modulates the direct effect of ethanol in the microvasculature; (b) that EDRF mediates the development of tolerance to the effect in microvessels; and (c) that the hypertension associated with chronic alcohol consumption is associated with the loss of EDRF activity. To test these hypotheses we initially propose to investigate the role of the endothelium in the action of alcohol in cerebral, mesenteric and cremaster muscle arterioles; these vessels have been observed to respond to physiological concentrations of ethanol. In addition, the effect of long term alcohol administration on the action of ethanol and its modulation by the endothelium will be investigated. A method of long term ethanol administration has been proposed which has been reported to induced mild hypertension. Subsequent studies are designed to evaluate the effect of chronic ethanol administration on the action of other vasoconstrictors and the role played by the endothelium in these effects. Finally, it is proposed that the association between changes in the sensitivity of the EDRF system and the development of hypertension during chronic ethanol administration be investigated. The long range goals of these studies are to obtain a better understanding of the effects of ethanol on the cardiovascular system and to described the mechanisms used to produced tolerance to these effects. Definition of these mechanisms may lead to new insights concerning the pathological effects of alcohol and their correction.